Neuronal mechanism for neuropathic pain.

Department of Physiology, Faculty of Medicine, University of Toronto Centre for the study of Pain, University of Toronto, Toronto, Ontario, Canada. min.zhuo@utoronto.ca

Abstract

Among different forms of persistent pain, neuropathic pain presents as a most difficult task for basic researchers and clinicians. Despite recent rapid development of neuroscience and modern techniques related to drug discovery, effective drugs based on clear basic mechanisms are still lacking. Here, I will review the basic neuronal mechanisms that maybe involved in neuropathic pain. I will present the problem of neuropathic pain as a rather difficult task for neuroscientists, and we may have to wait for a long time before we fully understand how brain encode, store, and retrieve painful information after the injury. I propose that neuropathic pain as a major brain disease, rather being a clinic problem due to peripheral injury.

Long-term potentiation of sensory excitatory synapses in adult mouse ACC. A. Current-clamp recordings to identify pyramidal neurons (upper) and interneurons (bottom) by current injections of -100, 0, and 100 pA. A labeled pyramid-like neuron was shown on the top right. RP: resting membrane potential. B. LTP was induced in pyramidal neurons (n = 15) in adult ACC by the pairing training protocol (indicated by an arrow). The insets show averages of 6 EPSCs 5 min before and 25 min after the pairing training (arrow). The dashed line indicates the mean basal synaptic responses. C. An example showing the long-lasting synaptic potentiation. Pairing training is indicated by an arrow. D. Basic synaptic transmission showing no change during recording without applying pairing training. The insets show averages of 6 EPSCs at the time points of 5 (pre) and 35 (post) min during the recording [Modified from 15].

Model of signaling pathways for LTP and central plasticity caused by injuries. A. In the ACC, activity triggers release excitatory neurotransmitter glutamate (Glu: filled circles). Activation of glutamate NMDA receptors leads to an increase in postsynaptic Ca2+ in dendritic spines. Ca2+ serves as an important intracellular signal for triggering a series of biochemical events that contribute to the expression of LTP. Neural Ca2+ binds to CaM and leads to activation of calcium-stimulated ACs, including AC1 and AC8 and Ca2+/CaM dependent protein kinases (PKC, CaMKII and CaMKIV). The Ca/CaM dependent protein kinases phorsphoryalte glutamate AMPA receptors, increasing their sensitivity to glutamate. B. In the ACC synapses, the possible postsynaptic trafficking of AMPA GluR1 receptors contributes to synaptic potentiation. C. Inflammatory or nerve injuries cause both presynaptic and postsynaptic changes in the ACC synapses. Enhanced release of glutamate as well as postsynaptic changes in AMPA receptor mediated responses contribute to enhanced noxious sensory information with in the brain, a possible cellular mechanism for persistent pain.

Positive feedback control as a key central mechanism for persistent pain. Sensory inputs inducing painful stimuli enter the brain through three major synaptic relays, including the dorsal horn (DH), thalamus and anterior cingulate cortex (ACC). At each synaptic relay, glutamate is the major fast excitatory transmitter. While AMPA and KA receptors mediate most of the synaptic response at resting conditions, NMDA receptors serve as a coincidence detector to enhance synaptic responses in an activity-dependent manner. Long-lasting potentiation is likely to occur at each sensory synapse. Within the ACCs, cortical connections may also undergo plastic changes, and may serve as highest central loci to store unpleasantness or pain. In addition, dorsal horn sensory synapses receive heterosynaptic facilitatory modulation from supraspinal structures, including the forebrain and brainstem. The RVM in the brainstem is likely to serve as a final relay for this descending facilitatory or excitatory modulation. Both homosynaptic and heterosynaptic enhancement will lead central sensory neurons to an enhanced excitatory status, so that a gentle trigger (for example, allodynia) or stimulation can cause massive firing of action potentials and thus cause pain. In the case of central pain, spontaneous activity of neurons in the network itself can also lead to action potential firing and pain.